Mutation Research/Reviews in Mutation Research
ReviewResponse of normal stem cells to ionizing radiation: A balance between homeostasis and genomic stability
Introduction
The presence of stem cells has been demonstrated at various development stages in normal mammalian tissues, which allowed characterizing embryonic, foetal and adult stem cells. Embryonic stem cells are taken from the embryo at 4 to 5 days after fertilization. Cells from foetal tissues, for example cord blood cells or germ cells isolated from the gonadal ridge, are isolated from 5 to 10 weeks foetuses. Finally, adult stem cells can be found in various tissues of fully developed children or adults, and particularly in organs showing continuous regeneration. Adult stem cells are defined as undifferentiated cells that can self-renew over very long periods of time, while producing cell progeny that mature into more specialized, organ-specific cells [1], [2], [3], [4]. They maintain long-term tissue homeostasis, the physiological process responsible for internal stability in renewing organs, including a constant number of cells. In normal conditions, most adult stem cells are slow cycling, resting in the G0 phase of the cell cycle. When they divide, it is through an asymmetric process, which produces one daughter cell with SC properties and one progenitor or transit-amplifying cell, undergoing a limited number of cell divisions before differentiation [5]. Asymmetric cell division allows adult stem cells to maintain homeostasis within a tissue throughout the lifetime of an organism, whereas a switch to symmetric cell division occurs when the stem cell pool needs to be expanded, or replenished, such as during body growth or wound healing. Hierarchical models have been proposed for several tissues, including blood, skin (Fig. 1) and intestinal tissue (Fig. 2), where tissue homeostasis entirely depends on rare, quiescent cells, which are vastly outnumbered by the dividing progenitor population, from which the differentiated cells are formed [6].
As adult SCs self-renew throughout life, accumulating genetic alterations can compromise their genomic integrity and potentially give rise to cancer. Stem cells may thus be a major target for genetic and epigenetic changes leading to radiation carcinogenesis [7]. Genomic instability is a hallmark of cancer development, with several putative mechanisms, including inaccurate repair of DNA lesions [8], [9] or telomere dysfunction [10] coupled with failure to stop cells progressing through their cycle. SCs may possess specific characteristics to avoid genomic instability. Some cell responses are efficient to decrease the risk of cell transformation, such as massive elimination of damaged cells, but can compromise lineage functionality. On the opposite, radiation resistance resulting in survival of cells with unrepaired damage can favor long-term accumulation of genetic anomalies. Response of adult stem cells to a genotoxic stress like ionizing radiation must then be a fine balance between maintenance of tissue homeostasis and genomic integrity. This review addresses normal stem cells’ response to ionizing radiation, focusing on intrinsic radiosensitivity, which measures early radiation toxicity, and on long-term consequences of radiation exposure. An excellent review on cancer stem cells has been recently published [11]. We first review embryonic stem cells as a paradigm of primitive pluripotent cells, and then three adult tissues, blood, skin and intestine, which are all capable of long-term regeneration and at high risk for acute radiation syndromes and long-term carcinogenesis.
Section snippets
Embryonic stem cells
Embryonic stem (ES) cells are transient cells present in the blastocyst, a structure formed at day 5 after fertilization in early human embryogenesis. They differentiate into the three germ layers and can form any of the over 200 cell types found in the body, thus governing all further embryonic development. When derived in tissue culture, ES cell lines produce rapidly proliferating cells keeping self-renewal and pluripotency [12], [13], [14]. ES cells never undergo asymmetric cell divisions
Bone-marrow stem cells
Adult bone marrow contains two major types of SC: hematopoietic (HSCs) and mesenchymal (MSCs). HSCs reside in adult bone marrow, a self-renewing tissue driven by a few stem and early progenitor cells (HPCs) that asymmetrically self-renew and differentiate into the three blood-cell types: leucocytes, erythrocytes and thrombocytes [27], [28]. Radiation biology played an historical role in defining these cells, as Till and McCulloch [1] provided the first evidence for their existence through
Skin
Skin is one of most sensitive tissues to ionizing radiation, and particularly epidermis. Despite improvements in radiation techniques [52], skin changes can be experimented by up to 95% of radiotherapy patients [53], and radiation toxicity cases are increasing after interventional radiology [54]. Thus the cellular origin of this sensitivity has been searched at the level of stem and progenitor cells. Skin is a potent stem cell reservoir. Different types, including epidermal, melanocyte,
Intestine
Radiation biology was the initial field where intestinal stem cells have been explored, because ionizing radiations induce an acute toxicity known as the gastrointestinal syndrome. Thus mice receiving greater than 14 Gy die between 7 and 12 days due to damage to the small intestine. This high sensitivity has been related to the fact that small intestinal mucosa is the organ with the fastest cell turnover in the body. In the murine small intestine, the epithelium renews every 5 days, due to the
Discussion
Stem cell research is a rapidly moving field of science that investigates self-renewing cells in adult and embryo. Many adult SCs have been identified, all crucial in supplying mature cells during normal homeostasis and tissue regeneration. A singular challenge today is to understand how they protect their genome from endogenous and exogenous injury. This protection is of a great importance for stem cell therapy, because expansion of stem cells to create cell banks requires genomic stability.
Conclusion
In the three adult tissues reviewed, which are all capable of long-term regeneration and characterized by a hierarchical organization, two types of radiation response emerge from the literature. In a first type, observed in bone marrow and skin, tissue maintenance is favored, as the rare stem cells appear more resistant than their daughter cells, the progenitors. The fact that both tissues are high risk for carcinogenesis suggests that genomic stability is not optimum, although DNA repair may
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
The present review benefited from the scientific support of the MELUSYN network. We thank Dr. Odile Rigaud and Dr. Nicolas Fortunel for carefully reading the manuscript. Our work was supported by funds from the CEA, Life Sciences Division, EDF (Comité de Radioprotection d’Electricité de France), and the ANR (BIRAD, ANR-05-SEST-026-03, LODORA, CESA-024-04).
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